<Emphasis Type="Italic">BRCA1 and BRCA2</Emphasis> mutation spectrum – an update on mutation distribution in a large cancer genetics clinic in Norway

Background

Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.

Methods

A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.

Results

There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.

Conclusions

The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway’s largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.

     

The Influence of Menopausal Hormone Therapy and Potential Lifestyle Interactions in Female Cancer Development—a Population-Based Prospective Study

The past decades have seen contradictory research results on the health benefits and risks of menopausal hormone therapy (HT). In particular, long-term associations with overall cancer incidence and the potential interplay with other lifestyle factors remain undetermined. In a population-based prospective cohort, 29,152 women aged 50–64 years at entry (1993–1997) were followed through 2013 for incidence of cancer (99% complete follow-up). Cox’ proportional hazards models were used to estimate cancer incidence according to baseline HT alone and in combination with lifestyle factors including alcohol intake, BMI, physical activity, diet, and smoking. Among 5484 women diagnosed with cancer, baseline HT was associated with an overall higher risk of cancer (HR 1.28; 95%CI, 1.21–1.36)—in particular, a higher risk of breast (HR 1.77; 95%CI, 1.61–1.95), ovarian (HR 1.68; 95%CI, 1.26–2.26), and endometrial (HR 1.86; 95%CI, 1.45–2.37) cancer. Combination with other lifestyle risk factors largely displayed additive associations. The risk of colorectal cancer was significantly lower (HR 0.79; 95%CI, 0.66–0.95). However, in the interaction analysis, only “healthy” subgroups of women using HT had a lower risk of colorectal cancer. With an overall higher risk of cancer among women on HT, this study underlined the importance of considering all female cancer risks in menopausal treatment guidelines. The largely additive associations between HT and the investigated lifestyle factors support the notion that high levels of hormones in itself play an important etiological role in female reproductive cancers, whereas the possible protective impact in colorectal cancer might be limited to women with an otherwise healthy lifestyle.     

Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer‐free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1–4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1–2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake.     

A prospective evaluation of plasma polyphenol levels and colon cancer risk

Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data linking specific polyphenols to colon cancer is limited. We assessed the relationship between pre‐diagnostic plasma polyphenols and colon cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted conditional logistic regression models that included established colon cancer risk factors. The false discovery rate (q_values) was computed to control for multiple comparisons. All statistical tests were two‐sided. After false discovery rate correction and in continuous log₂‐transformed multivariable models, equol (odds ratio [OR] per log₂‐value, 0.86, 95% confidence interval [95% CI] = 0.79–0.93; q_value = 0.01) and homovanillic acid (OR per log₂‐value, 1.46, 95% CI = 1.16–1.84; q_value = 0.02) were associated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR = 0.61, 95% CI = 0.41–0.91, p_trend = 0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR = 1.72, 95% CI = 1.17–2.53, p_trend < 0.0001). No heterogeneity for these associations was observed by sex and across other colon cancer risk factors. The remaining polyphenols were not associated with colon cancer risk. Higher equol concentrations were associated with lower risk, and higher homovanillic acid concentrations were associated with greater risk of colon cancer. These findings support a potential role for specific polyphenols in colon tumorigenesis.